Categories: Muscle phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 176290 (gene) , 613648 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal

Disease-related: no

Key variant known: yes

Year key variant first reported: 2002

Cross-species summary: Abnormal increase in muscular tissue caused entirely by enlargement of existing cells (in contrast to muscular hyperplasia, in which the abnormal increase in muscular tissue is due to the formation and growth of new, normal muscle cells)

Species-specific name: Callipyge

Species-specific symbol: CLPG

Species-specific description: This trait was first reported in sheep by Cockett et al. (1994), who showed that the locus at which this potentially advantageous mutation occurred is on chromosome 18, near the non-centromeric end. The mutant allele leads to increased protein synthesis and decreased protein degradation. The practical effects include higher dressing percentage, reduced fat thickness, and reduced marbling, while carcass weight is not affected (Koohmaraie et al., 1995; 1996; Carpenter et al., 1996). Overall, callipyge lambs have a distinct advantage in retail yield and carcass conformation (Jackson et al., 1997b), with the increased muscle mass being concentrated in the leg and loin (Jackson et al., 1997c). Jackson et al. (1997a) showed that callipyge lambs have a lower feed intake than non-callipyge lambs, but the same growth rate. Consequently, callipyge lambs have a superior feed efficiency. Greasy fleece weight and staple length of callipyge lambs were slightly lower.

History: The trait was first observed in 1983 by a sheep producer who noticed a Rambouillet ram with extreme muscling (Cockett et al., 1994). After showing via breeding experiments that this trait is single-locus autosomal, Cockett et al. (1994) proposed the name "callipyge (from Greek calli-, beautiful; -pyge buttocks)" and the symbol CLPG.

Inheritance: A distinctive feature of this type of muscular hypertrophy is its unusual mode of inheritance: the only animals with the phenotype are heterozygotes who inherited the mutant allele from their sire. Cockett et al. (1996) suggested the term polar overdominance for this form of inheritance, which is likely to be the result of a form of imprinting.

Mapping: In the absence of any useful sheep markers, Cockett et al. (1994) conducted a "genome scan" with just four(!) bovine minisatellites (VNTRs), two of which had no known bovine map location, the other two of which were known to be located on bovine chromosomes BTA21 and BTA26. To the authors' understandable surprise (not to mention extraordinary luck), the BTA21 marker (GMBT16) showed linkage with the CLPG locus! Linkage analysis in additional families confirmed that GMBT16 is linked to CLPG with theta = 20%. Since GMBT16 had also been ISH-mapped to the pro-terminal region of sheep homologous chromosome OVA18, Cockett et al. (1994) had succeeded in mapping the CLPG locus! The same authors then used bovine microsatellites and additional bovine minisatellites, all known to be on BTA21, to fine-map the CPLG locus to within 3 cM of bovine microsatellite CSSM18 on OVA18. Freking et al. (1998) confirmed the map location of CLPG in a resource flock derived from Dorset rams and Romanov ewes. Extensive fine-mapping effort in the following years finally yielded two ovine BACs and a connecting PCR product that together spanned a 250kb region including the CLPG locus (Charlier et al. (2001). Sequencing of this region revealed six imprinted transcripts: "DLK1, DAT, and PEG11 were shown to be paternally expressed and GTL2, antiPEG11, and MEG8 to be maternally expressed". Four of these (PEG11, MEG8, asDAT and antiPEG11) were novel genes.

Markers: The gene is located between two microsatellite markers; 12 cM from one and 19cM from the other (Shay et al., 1998)

Molecular basis: Sequencing within the refined candidate region (described in the Mapping section above) enabled Freking et al. (2002) to identify the causative mutation as a "a single A/G polymorphism located at position 103,894 of GenBank AF354168 and position 267 of the GenBank STS AF401294". A few months later, Smit et al. (2003), working on in an independent sheep resource, identified the same mutation, which they described as "an A-to-G transition in a highly conserved dodecamer motif between DLK1 and GTL2". By 2010, knowledge of this most unusual mutant could be summarised as follows. "The mutation is a base substitution in a non-coding section of a 90-kb region of DNA that contains six genes: DLK1, DAT, and PEG11 have paternal allele-specific expression whereas GTL2, PEG11AS and MEG8 are expressed from the maternal allele. When an animal inherits the callipyge mutation from its sire but not its dam, the mutation increases the expression of the DLK1 and PEG11 genes on the same (paternal) chromosome; the mutation is said to be cis-acting. The increased expression of these two genes is associated with the muscle hypertrophy of the callipyge trait." (Nicholas, 2010; Introduction to Veterinary Genetics, Wiley-Blackwell, Oxford; p. 202)

Breed: Rambouillet (Sheep) (VBO_0001570).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: